21st Century cGMP

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 GMP REGULATIONS

 ICH GUIDANCE REQUIREMENT

 Stability studies
 Analytical method validation
 Impurities
 Pharmacopeias
 GMP for Biotechnological products
 Specifications
 GMP for APIs
 Pharmaceuticals development
 Quality risk management
 Pharmaceuticals quality system
 Development and manufacturing of drug substances
 Product life cycle management (Draft)

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 PROCESS VALIDATION

 PROCESS VALIDATION (USFDA)

 Process Design (Stage-1)

1. Building and Capturing Process Knowledge and Understanding (DOE)
2. Establishing a Strategy for Process Control (PAT)
 The commercial manufacturing process is defined during this stage based on knowledge gained
through development and scale-up activities

 Process Performance Qualification (Stage-2)

1. Design of a Facility and Qualification
of Utilities and Equipment
2. Process Performance Qualification
3. PPQ Protocol
4. PPQ Protocol Execution and Report

 During this stage, the process design is evaluated to determine if the process is capable of
reproducible commercial manufacturing.

 Continuous Process Verification (Stage-3)

Ongoing assurance is gained during routine production that the process remains in a state of control.

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 QUALITY METRICS

 QUALITY METRICS

 LAR (Manufacturing performance Indicator)

 The number of accepted lots in a timeframe divided by the number of lots started by the same
covered establishment in the current reporting timeframe.

 IOOSR (Laboratory performance Indicator)

 The number of OOS test results for lot release and long-term stability testing invalidated by the
covered establishment due to an aberration of the measurement process divided by the total
number of lot release and long-term stability OOS test results in the current reporting timeframe.

 PQCR (Customer feedback Indicator)

 The number of product quality complaints received for the product divided by the total number
of dosage units distributed in the current reporting timeframe.

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 PROCESS ANALYTICAL TECHNOLOGY

 PAT
 PAT principles and tools should be introduced during the development phase.
 The goal of PAT is to enhance understanding and control the manufacturing process, which is
consistent with our current drug quality system: “quality cannot be tested into products; it should
be built-in or should be by design”.
 A process is generally considered well understood when (1) all critical sources of variability are
identified and explained; (2) variability is managed by the process; and, (3) product quality
attributes can be accurately and reliably predicted over the design space established for materials
used, process parameters, manufacturing, environmental, and other conditions.
 Reducing production cycle times by using on-, in-, and/or at-line measurements and controls
 Preventing rejects, scrap, and re-processing
 Real time release
 Increasing automation to improve operator safety and reduce human errors
 Improving energy and material use and increasing capacity
 Facilitating continuous processing to improve efficiency and manage variability

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 QUALITY BY DESIGN

 QbD

ICH Q8(R2) defines QbD as “a systematic approach to development that begins with predefined
objectives and emphasizes product and process understanding and process control, based on sound
science and quality risk management”.

The application of QbD in pharmaceutical product development is systematic, involving multivariate

experiments utilizing process analytical technology (PAT) and other tests to identify critical quality
attributes (CQAs), CPPs, CMAs based on risk assessments (RAs).

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 QUALITY RISK MANAGEMENT

Risk Ranking Risk Factors

Qualitative Quantitative Severity (S) Probability (P) Detectability (D)

Unlikely probability of Obvious or alarmed

Irrelevant 1 No impact to the patient safety
occurrence automatically

Remote probability of Automated, sensor

Low 2 Minor irritation
occurrence. based system
Inspection or
Occasional probability of
Moderate 3 Reversible effect statistical based
occurrence
sampling
May cause adverse effect or Moderate probability of
High 4 Manual system
birth defects occurrence

Can cause death or severe High probability of Not detected by

Very High 5
disabilities to the patient occurrence current methods

 A product of S x P x D will result is a number called as the Risk Priority Number (RPN).
• Low Risk- 1-25
• Medium Risk-26-64
• High Risk-65 and above

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 CONTINUOUS IMPROVEMENT

 FDA expecting continuous Improvement instead of Corrective Actions

 Development of a deep understanding of the processes
 Effective and efficient design of the manufacturing processes
 Critical sources of variability in the manufacturing process to be identified and explained
 These variability's then to be controlled in the manufacturing processes
 And therewith the quality of the product (with the variability as small as possible) to be reliably
predictable (Process Capability)
 Continuous real-time measurements
 Statistical process control
 Learning from previous discrepancies
 Zero defects

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 EQUIPMENT QUALIFICATION

 User requirements specification (URS)

The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a
functional specification.

 Design qualification (DQ)

Design specification and functional specifications (DS & FS).

 Factory acceptance testing (FAT)

Prior to installation, equipment should be confirmed to comply with the URS/functional specification
at the vendor site. FAT protocol shall be written by the customer and executed by vendor.

 Site acceptance testing (SAT)

SAT following the receipt of equipment at the manufacturing site. This is written by the client and
verifies that the installed functionality of the equipment meets or exceeds the operational
requirements as specified in the equipment URS. The SAT is executed on completion of all
commissioning tasks; but prior to the start of Installation Qualification execution.

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 PRODUCT LIFE CYCLE MANAGEMENT (ICH Q12)
 POST-APPROVAL CHANGE MANAGEMENT PROTOCOL (PACMP)
 A PACMP is a regulatory tool that provides predictability and transparency in terms of the requirements
and studies needed to implement a change as the approved protocol provides an agreement between the
MAH and the regulatory authority.

 A protocol describes the CMC change an MAH intends to implement during the commercial phase of a
product, how the change would be prepared and verified, including assessment of the impact of the
proposed change, and the suggested reporting category in line with regional requirements, i.e., a lower
reporting category and/or shortened review period as compared to similar change procedure without an
approved PACMP.

 The PACMP also identifies specific conditions and acceptance criteria to be met.

 PACMP can address one or more changes for a single product, or may address one or more changes to be
applied to multiple products.

 The PACMP may be submitted with the original MAA or subsequently as a stand-alone submission. The
PACMP requires approval by the regulatory authority, and the conditions and acceptance criteria outlined
in the protocol must be met in order to implement the change(s).

 Based on an initial risk assessment, a list of specific tests and studies to be performed to evaluate the
potential impact of the proposed change(s), such as: characterization, batch release, stability, in-process
controls. The PACMP should include an appropriate description of the analytical procedures and proposed
acceptance criteria for each test or study.

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 PRODUCT LIFE CYCLE MANAGEMENT

 PRODUCT LIFECYCLE MANAGEMENT (PLCM)

 The PLCM document outlines the specific plan for product lifecycle management that is proposed
by the MAH, includes key elements of the control strategy, the ECs (Established Conditions),
proposed reporting categories for changes to ECs, PACMPs (if used) and any post approval CMC
commitments. This will encourage prospective lifecycle management planning by the MAH and
facilitate regulatory assessment and inspection. The PLCM document should be updated
throughout the product lifecycle as needed.

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 FDA 483 REPEATED OBSERVATIONS

Total observations-315 & Repeated observations-196

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Kumar Veeramalla

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